Two-step continuous flow aerobic oxidation of cannabidiol to cannabinoquinone derivatives

Abstract

A two-step continuous flow oxidation procedure is presented for the preparation of Etrinabdione, a cannabidiol quinone derivative. Etrinabdione is currently undergoing clinical trials for the treatment of peripheral artery disease. Both steps described herein utilize molecular oxygen as a green and inexpensive stoichiometric oxidant. Initially, the two-steps were optimized separately. The first step is a very fast oxidation process to form quinonoid derivative HU-331 and includes an in situ quench for the safe handling of peroxy intermediates. The second step is a segmented flow oxidative amination to afford Etrinabdione. The two steps can be run either separately or telescoped by incorporating a gravity-based continuous separation. The two steps were telescoped to afford Etrinabdione in 98% yield. The process mass intensity (PMI) was significantly reduced when compared to an existing batch protocol. The second step was also adapted for the preparation of two additional cannabidiol quinone analogs. The described protocol significantly improves the efficiency, safety and scalability when compared to existing batch protocols.